Recent studies from this laboratory have conclusively established that surgical stress results in a marked and persistent hypocitricemia in virtually all patients. One might expect that this response is due to the hypocitricemic effect of cortisol which is elevated during surgery. However the plasma cortisol levels do not appear to correlate with the citrate response in a manner that would clearly establish this relationship. Consequently two significant areas need to be resolved: 1) the agent or mediator of the hypocitricemia must be identified; 2) the mechanism by which the circulating citrate level is decreased must be ascertained. Patient studies will be utilized in one phase of the program. Simultaneous measurements of plasma and urine changes following surgery will be made. From this study the possible relationship of altered citrate clearance (renal involvement in citrate regulation) to the plasma citrate level will be establishd. Also urinary excretion of cortisol (II-OHCS) will be determined as a better index of adrenal corticol response than plasma levels. We will also study the hypocitricemic effect of cortisol injected into normal subjects in order to relate this response to surgical stress. A second phase of the investigation will include experimental animals. Preliminary studies indicate that the dog and rat also elicits a hypocitricemic response to surgery. With such a model, studies on the effects of surgical stress and adrenocorticoids on renal citrate handling will be ascertained as well as correlations with the patient response. Additionally the possible involvement of anaesthesia in the hypocitricemic effect will be determined. Appropriate animal and human studies should resolve the questions concerning this hypocitricemic response to surgery. The possible alteration in citrate oxidation by renal cortex will be studied as a possible mechanism associated with the decrease in circulating citrate.